1. Field of the Invention
The present invention relates to polymer compositions containing bioactive agents and methods for their use. Such compositions can be used to coat medical devices such as intravascular stents.
2. Description of Related Art
A wide variety of medical conditions are treated by introducing an implantable medical device partly or completely into the esophagus, trachea, colon, biliary tract, urinary tract, vascular system or other location within a human or veterinary patient. For example, many treatments of the vascular system entail the introduction of a device such as a stent, a catheter, a balloon, a wire guide, a cannula, or the like. However, when such a device is introduced into and manipulated through the vascular system, the blood vessel walls can be disturbed or injured. Clot formation or thrombosis often results at the injured site, causing stenosis or occlusion of the blood vessel. Moreover, if the medical device is left within the patient for an extended period of time, thrombus often forms on the device itself, again causing stenosis or occlusion. As a result, the patient is placed at risk of a variety of complications, including heart attack, pulmonary embolism, and stroke. Thus, the use of such a medical device can entail the risk of precisely the problems that its use was intended to ameliorate.
Another way in which blood vessels undergo stenosis is through disease. Probably the most common disease causing stenosis of blood vessels is atherosclerosis. Atherosclerosis is a condition which commonly affects the coronary arteries, the aorta, the iliofemoral arteries and the carotid arteries. Atherosclerotic plaques of lipids, fibroblasts, and fibrin proliferate and cause obstruction of an artery or arteries. As the obstruction increases, a critical level of stenosis is reached, to the point where the flow of blood past the obstruction is insufficient to meet the metabolic needs of the tissue distal to (downstream of) the obstruction. The result is ischemia.
Many medical devices and therapeutic methods are known for the treatment of atherosclerotic disease. One particularly useful therapy for certain atherosclerotic lesions is percutaneous translummnal angioplasty (PTA). During PTA, a balloon-tipped catheter is inserted in a patient""s artery, the balloon being deflated. The tip of the catheter is advanced to the site of the atherosclerotic plaque to be dilated. The balloon is placed within or across the stenotic segment of the artery, and then inflated. Inflation of the balloon xe2x80x9ccracksxe2x80x9d the atherosclerotic plaque and expands the vessel, thereby relieving the stenosis, at least in part.
While PTA presently enjoys wide use, it suffers from two major problems. First, the blood vessel may suffer acute occlusion immediately after or within the initial hours after the dilation procedure. Such occlusion is referred to as xe2x80x9cabrupt closure.xe2x80x9d Abrupt closure occurs in perhaps five percent or so of the cases in which PTA is employed, and can result in myocardial infarction and death if blood flow is not restored promptly. The primary mechanisms of abrupt closures are believed to be elastic recoil, arterial dissection and/or thrombosis. It has been postulated that the delivery of an appropriate agent (such as an antithrombic agent) directly into the arterial wall at the time of angioplasty could reduce the incidence of thrombotic acute closure, but the results of attempts to do so have been mixed. A second major problem encountered in PTA is the re-narrowing of an artery after an initially successful angioplasty. This re-narrowing is referred to as xe2x80x9crestenosisxe2x80x9d and typically occurs within the first six months after angioplasty. Restenosis is believed to arise through the proliferation and migration of cellular components from the arterial wall, as well as through geometric changes in the arterial wall referred to as xe2x80x9cremodeling.xe2x80x9d It has similarly been postulated that the delivery of appropriate agents directly into the arterial wall could interrupt the cellular and/or remodeling events leading to restenosis. However, like the attempts to prevent thrombotic acute closure, the results of attempts to prevent restenosis in this manner have been mixed. Non-atherosclerotic vascular stenosis may also be treated by PTA. For example, Takayasu arteritis or neurofibromatosis may cause stenosis by fibrotic thickening of the arterial wall. Restenosis of these lesions occurs at a high rate following angioplasty, however, due to the fibrotic nature of the diseases. Medical therapies to treat or obviate them have been similarly disappointing.
A device such as an intravascular stent can be a useful adjunct to PTA, particularly in the case of either acute or threatened closure after angioplasty. The stent is placed in the dilated segment of the artery to mechanically prevent abrupt closure and restenosis. Unfortunately, even when the implantation of the stent is accompanied by aggressive and precise antiplatelet and anticoagulation therapy (typically by systemic administration), the incidence of thrombotic vessel closure or other thrombotic complication remains significant, and the prevention of restenosis is not as successful as desired. Furthermore, an undesirable side effect of the systemic antiplatelet and anticoagulation therapy is an increased incidence of bleeding complications, most often at the percutaneous entry site.
Other conditions and diseases are treatable with stents, catheters, cannulae and other devices inserted into the esophagus, trachea, colon, binary tract, urinary tract and other locations in the body, or with orthopedic devices, implants, or replacements. Consequently, it would be desirable to develop devices and methods for reliably delivering suitable agents, drugs or bioactive materials directly into a body portion during or following a medical procedure, so as to treat or prevent such conditions and diseases, for example, to prevent abrupt closure and/or restenosis of a body portion such as a passage, lumen or blood vessel. As a particular example, it would be desirable to have devices and methods which can deliver an antithrombic or other medication to the region of a blood vessel which has been treated by PTA, or by another interventional technique such as atherectomy, laser ablation, or the like.
There is a need in the art for improved compositions and methods that can be used with implantable medical devices to deliver bioactive agents at a site of implantation (e.g. a blood vessel which has been treated by PTA). Embodiments of the invention disclosed herein satisfy this need.
A discovery underlying the present invention is the incorporation of bioactive agents in polymer compositions, such as silicon containing siloxanes, in the formation of biocompatible coatings for medical devices such as stents. The polymer compositions can be used in conjunction with a variety of compounds for the preparation of coatings in which the movement of both endogenous and exogenous analytes and reactive species through the coatings (e.g., chemokines, immunosuppressive and/or anti-inflammatory agents) can be controlled. The coatings produced from these components are typically homogeneous and are useful for coating a number of devices designed for implantation.
The invention disclosed herein has a number of embodiments. A preferred embodiment of the invention is an implantable medical device having at least one polymer coating composition, the polymer coating prepared from a reaction mixture of a diisocyanate, the diisocyanate comprising about 50 mol % of the reactants in the mixture, a hydrophilic polymer which is a member selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof, a bioactive agent; and optionally a chain extender. In preferred embodiments, the reaction mixture further comprises a siloxane polymer having functional groups at the chain termin, typically amino, hydroxyl and carboxylic acid groups. A specific embodiment of the invention includes a polymer coating having a water pickup of from about 25% to about 400% by weight. In yet another embodiment, the polymer coating has a glucose diffusion coefficient of from about 1xc3x9710xe2x88x929 cm2/sec to about 200xc3x9710xe2x88x929 cm2/sec, and a ratio of Doxygen/Dglucose of from about 5 to about 2000.
In illustrative embodiments of the invention, the diisocyanate used in the reaction mixture is selected from the group consisting of isophorone diisocyanate, 1,6-hexamethylene diisocyanate and 4,4xe2x80x2-methylenebis(cyclohexyl isocyanate). In embodiments of the invention that utilize a chain extender, preferably the chain extender is selected from the group consisting of an alkylene diol, an alkylene diamine, an aminoalkanol and combinations thereof. In a preferred embodiment of the invention, the diisocyanate is 1,6-hexamethylene diisocyanate, the hydrophilic polymer is selected from the group consisting of PEG 400 and PEG 600 and is present in an amount of about 17 to about 32 mol %, and the siloxane polymer is aminopropyl polysiloxane having a molecular weight of about 2000 to about 4000 and is present in an amount of about 17 to about 32 mol %.
A related embodiment of the invention is a polymer composition formed by admixing a diisocyanate, the diisocyanate comprising about 50 mol % of the reactants in the admixture, a hydrophilic polymer selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof, a bioactive agent and optionally, a chain extender. Yet another embodiment of the invention is a method for making a polymer composition, the method comprising: admixing a diisocyanate, the diisocyanate comprising about 50 mol % of the reactants in the admixture, a hydrophilic polymer selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof, a bioactive agent and, optionally, a chain extender, thereby forming the polymer composition.
In preferred embodiments of the invention, the bioactive agent is capable of being released from the polymer coating into the environment in which the medical device is placed. Moreover, as described herein, the reagents and reaction conditions of the polymer compositions can be manipulated so that the release of the bioactive agent from the polymer coating can be controlled. For example, the diffusion coefficient of the one or more polymer coatings can be modulated to control the release of the bioactive agent from the polymer coating. In a variation on this theme, the diffusion coefficient of the one or more polymer coatings can be controlled to modulate the ability of an analyte that is present in the environment in which the medical device is placed (e.g. an analyte that facilitates the breakdown or hydrolysis of some portion of the polymer) to access one or more components within the polymer composition (and for example, thereby modulate the release of the bioactive agent from the polymer coating). Yet another embodiment of the invention includes a device having a plurality of polymer coatings, each having a plurality of diffusion coefficients. In such embodiments of the invention, the release of the bioactive agent from the polymer coating can be modulated by the plurality of polymer coatings.
In yet another embodiment of the invention, the release of the bioactive agent from the polymer coating is controlled by modulating one or more of the properties of the polymer composition such as the presence of one or more endogenous or exogenous compounds, or alternatively, the pH of the polymer composition. For example, certain polymer compositions disclosed herein can be designed to release a bioactive agent in response to a decrease in the pH of the polymer composition. Alternatively, certain polymer compositions disclosed herein can be designed release a bioactive agent in response to the presence of hydrogen peroxide.
Illustrative embodiments of the invention incorporate glucose oxidase into the polymer composition, a protein which reacts with glucose and oxygen to generate gluconolactone and hydrogen peroxide. The gluconolactone produced by this process then further reacts with water to hydrolyze the lactone ring and produce gluconic acid. A specific example of this embodiment of invention is an implantable medical device having at least one polymer coating composition, the polymer coating prepared from a reaction mixture of a diisocyanate, the diisocyanate comprising about 50 mol % of the reactants in the mixture, a hydrophilic polymer which is a member selected from the group consisting of a hydrophilic polymer diol, a hydrophilic polymer diamine and combinations thereof, glucose oxidase, a bioactive agent wherein the bioactive agent is capable of being released from the polymer coating into the environment in which the medical device is placed, and wherein the bioactive agent is an anti-thrombocytic, anti-inflammatory or anti-proliferative agent. In this embodiment, the release of the bioactive agent is modulated by a product that is produced from a reaction between the glucose oxidase that is present in the polymer coating and glucose (a typical analyte that facilitates the breakdown or hydrolysis of some portion of a polymer coating) that is present in the environment in which the medical device is placed. In a preferred embodiment the product that modulates the release of the bioactive agent is gluconic acid. Alternatively the product that modulates the release of the bioactive agent is hydrogen peroxide. Optionally a diffusion coefficient of one or more polymer coatings is manipulated to control the rate at which an analyte such as glucose diffuses through the polymer (thereby controlling the interaction between glucose and glucose oxidase).
A wide variety of medical devices can be coated with the polymer compositions disclosed herein. In preferred embodiments of the invention, the device is a stent, an infusion pump, a glucose sensor, a catheter, a balloon, a wire guide, a cannula or the like. In highly preferred embodiments, the device is an intravascular stent. In addition, a wide variety of bioactive agents can be incorporated into the polymer compositions disclosed herein. In preferred embodiments of the invention the bioactive agent is an anti-thrombocytic, anti-inflammatory or anti-proliferative agent. In highly preferred embodiments of the invention, the bioactive agent is rapamycin or heparin.